phenoxybenzamine

[MudPhud20XX]

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Firecracker says phenoxybenzamine (a nonselective alpha blocker) is the drug of choice for pheochromocytoma, but shouldn't you want to use selective alpha 1 blocker for pheochromocytoma? Since blocking alpha 2 will rather do the opposite (inhibiting the negative feed back on NE release by alpha 2)?

Many thanks in advance.

 

[notbobtrustme]

probably has poor CNS penetration, where the majority of a2 receptors are

 

[Missorleans]

Idk, but part of the benefit of phenoxybenzamine is that it is irreversible, so no matter how much NE the pheo puts out, still won't cause hypertension during the surgery.

 

[Bancrofti]

It says in the topic a major reason: longer duration of action. The half life of your prototypical selective alpha 1 blocker like Prazosin is around 4 hours. Phenoxybenzamine has a half life around 24 hours. You want to give it even before the surgery to remove the Pheo to antagonize the alpha 1 effect in preparation. If I had to assume why, it's that the hypertensive episodes associated with pheochromocytoma can occur at random times or with stress etc. A drug that antagonizes the catecholamine effect for the whole day will be much better at managing the issue since it controls it at all times than something that only lasts for a 4 hours and may need to be taken multiple times.

And as said above, it doesn't really matter that it blocks alpha 2 as well, since you have irreversible blockage of alpha 1 also, there won't be stimulation even if there was catecholamine release due to feedback.

 

[ulikedaggers]

Firecracker says phenoxybenzamine (a nonselective alpha blocker) is the drug of choice for pheochromocytoma, but shouldn't you want to use selective alpha 1 blocker for pheochromocytoma? Since blocking alpha 2 will rather do the opposite (inhibiting the negative feed back on NE release by alpha 2)?

Many thanks in advance.

I've only seen the card where it emphasizes that phenoxybenzamine is an irreversible alpha blocker. With Pheo your focus isn't on inhibiting NE release, it's preventing hypertensive crisis.

 

[jschirripa]

Firecracker says phenoxybenzamine (a nonselective alpha blocker) is the drug of choice for pheochromocytoma, but shouldn't you want to use selective alpha 1 blocker for pheochromocytoma? Since blocking alpha 2 will rather do the opposite (inhibiting the negative feed back on NE release by alpha 2)?

Many thanks in advance.

Phenoxybenzamine is not only a nonselective alpha antagonist but its a noncompetitive inhibitor. No matter how much NE and Epi you pump out of the adrenals phenoxybenzamine will not be displaced/pushed out of the way throughout the body and allow you to pump the brakes on the sympathetic effects.

 

[dyspareunia]

Phenoxybenzamine is not only a nonselective alpha antagonist but its a noncompetitive inhibitor. No matter how much NE and Epi you pump out of the adrenals phenoxybenzamine will not be displaced/pushed out of the way throughout the body and allow you to pump the brakes on the sympathetic effects.

It's more important that it is irreversible. Some non-competitive inhibitors are reversible.

 

[Transposony]

Phenoxybenzamine is not only a nonselective alpha antagonist but its a noncompetitive inhibitor.

It is an irreversible competitive antagonist.

 

[Transposony]

Few more points since we are on the topic:

1. Phenoxybenzamine is started about 2 weeks before the surgery.
2. Beta blockers are started AFTER phenoxybenzamine is up and running to control tachycardia due to phenoxybenzamine.
3. Phentolamine or selective alpha 1 blocker (Prazosin) are used during surgery (since you don't want their BP to plummet once Pheo comes out).

And most important of all- You fill them up with saline and/or salty diet days before surgery since they are severely volume depleted.

 

[thehundredthone]

To add to Transposony. Pheochromocytoma can present with orthostatic hypotension due to the volume depletion despite them being vasoconstricted when NE is released.

 

[dyspareunia]

Few more points since we are on the topic:

1. Phenoxybenzamine is started about 2 weeks before the surgery.
2. Beta blockers are started AFTER phenoxybenzamine is up and running to control tachycardia due to phenoxybenzamine.
3. Phentolamine or selective alpha 1 blocker (Prazosin) are used during surgery (since you don't want their BP to plummet once Pheo comes out).

And most important of all- You fill them up with saline and/or salty diet days before surgery since they are severely volume depleted.

Can you explain how phentolamine prevents hypotension?

 

[Transposony]

Can you explain how phentolamine prevents hypotension?

Phentolamine is a reversible alpha blocker. So, you titrate it's dose against BP intraoperatively and stop it once the Pheo is out and BP has stabilized.

 

[surgok]

It is an irreversible competitive antagonist.

just a small point, but FA erratum regarding phenoxybenzamine says it's a irreversible non-competitive antagonist.

 

[notbobtrustme]

It is an irreversible competitive antagonist.

if it's irreversible, by definition, it's non-competitive. How are you going to push it off the receptor? You can't, since it's covalently bound to the receptor, meaning you need to wait until the cell makes new receptors and recycles the old ones off.

 

[Transposony]

just a small point, but FA erratum regarding phenoxybenzamine says it's a irreversible non-competitive antagonist.

if it's irreversible, by definition, it's non-competitive. How are you going to push it off the receptor? You can't, since it's covalently bound to the receptor, meaning you need to wait until the cell makes new receptors and recycles the old ones off.

Thanks for correcting me.
What was I (not) thinking?
Typical example of memorization v/s understanding the mechanism.

 

[MDMikeRyan]

I have had this same problem. I started drawing the mechanism of action of the two non selective alpha blockers: Phenoxybenzamine and Phentolamine. My problem is that if pheochromocytoma has an already increase cathecolamine production in excess which causes enhancement of vasoconstriction by alpha 1 and beta 1 ( hypertension and increased heart rate) why give a non selective alpha antagonist/blocker if it also inhibits alpha 2 which functions as modulatory/regulatory enzyme which blocks the release of noepinephrine in the synaptic cleft. If you give an alpha blocker you will also increase more cathecolamine release and inhibit reuptake of norepinephrine by NET. This will enhance beta-1 adrenegernic receptor action in heart ( increase heart rate will lead to tachycardia and eventually atrial fibrillation), also it will increase water and salt retention in kidney reabsoprtion ( increase renin release) which it will negate hypotensive effect of alpha 1 blockade. While some of you put out a half answer saying that phenoxybenzamine is a non competitive irreversible drug that it will take 24-48 hrs to for new added receptors to work, it will only exert effect on hypertension, but it will exacerbate tachycardia, this could be deadly. This is why you administer beta blockers after alpha blockade, to control heart rate. In 2017 a new england journal article mention that use non selective alpha blockade has been eliminated in some countries because of the tachycardia exarcebation, and alpha-1 blockers have been the prefer method of treatment, specially doxazosin. The problem with the treatment with alpha-1 blockers is that all are reversible competitive drugs, meaning that if the concetration of cathecolamines is bigger than the effect of the drug it will still increase the hypertension and increasing the dosage will lead to more side effects. And alpha-1 blockers and alpha-2 agonist are never first line treatment for severe hypertension, they are only use concomitant with other antihypertensives because the decrease is progressive not inmmediately and your trying to prevent end-organ damage, ACV, infarct. I hope it clarifies some things even if it does not answer properly the problem.